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Simvastatin is a hypolipidemic drug used to control hypercholesterolaemia. It is a semi-synthetic statin based on lovastatin (NICE 2008). It is licensed to be used for the treatment of Primary hypercholesterolaemia, mixed dyslipidaemia, homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments and the reduction of cardiovascular mortality and morbidity (NICE 2008).
Simvastatin is given orally in a usual initial dose of 10-20mg in the evening; and an initial dose of 40mg in patients with high risk of cardiovascular disease (CVD). Simvastatin is an inactive lactone and is hydrolyzed in the liver to the active form beta-hydroxyacid, which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy-3 methylglutaryl CoA reductase) enzyme, which converts HMG-CoA to mevalonate, which enhances cholesterol synthesis. Statins (HMG-CoA reductase inhibitor) inhibit this process, which reduces cholesterol synthesis in the liver and lowers intracellular cholesterol concentrations; this stimulates an increase in low density lipoprotiens (LDL)-cholestrol receptors on the hepatocyte membrane, thereby increasing clearance of LDL from the circulation. The above process leads to an overall reduction in LDL, total cholestrol (TC), very-low-density lipoprotein (VLDL)-cholestrol and triglycerides (TG) concentrations in plasma and also increases high-density lipoprotein (HDL) concentrations.
Figure 1: Diagram of the mechanism by which statin lower blood cholestrol levels (American Heart Association)
Simvastatin in an inactive lactone form in the gastrointestinal tract, which is hydrolyzed to its active β-hydroxyacid. Hydrolysis takes place in the liver and the rate in human plasma is very slow.
Simvastatin is well absorbed in man and undergoes an extensive first-pass metabolism in the liver, its primary site of action. Following an oral dose of Simvastatin, less than 5% of the dose was found in the systemic circulation as active metabolites. Maximum plasma concentrations of the active inhibitors are reached approximately 1-2 hours after administration of Simvastatin.
Both Simvastatin and its active β-hydroxyacid metabolite are about 95% bound to plasma proteins. Statins are competitive antagonist of HMG-CoA, as they directly compete with the active site cavity of HMGR. Statins are also non-competitive with the co-substrate NADPH (nicotinamide adenine dinucleotide phosphate).The binding of the statins to the proteins is reversible. By blocking the HMGR enzyme they inhibit the synthesis of cholestrol, hence low LDL, TC and an increase in HDL.
Simvastatin is a substrate of cytochrome P450 (CYP450) isoenzyme CYP3A4 and is metabolised in the liver. CYP450 is the most potent metabolite of Simvastatin.When hydrolysis occurs in the liver microsomes, Simvastatin β-hydroxyacid(SVA) forms three to four metabolites, (CYP3A4, CYP3A5 and CYP2C8) and recombinant CYP3A4 and CYP3A5 are the most active forms. Studies show that CYP2C8 did not metabolize the β-hydroxyacid; hence 80% of the SVA metabolism in human liver microsomes is catalysed by CYP3A4 and CYP3A5, with a minor contribution (20%) from CYP2B8 (Prueksaritanont 2003)
Simvastatin is mainly excreted in the faeces via the bile as metabolites. About 10% to 15% is recovered in the urine, mainly in inactive forms. The half-life of the active β-hydroxyacid metabolite is 1.9 hours (Sweetman 2007).
Martindale: The Complete Drug Reference, 35th edition, Sweetman, S., 2007, Pharmaceutical Press, Volume 1, Pg: 1249 - 1251
Simvastatin is used to treat patients with primary hypercholesterolaemia, homozygous familial hypercholesterolaemia or combined hyperlipidaemia in patients who have not responded adequately to diet and other appropriate measures; prevention of cardiovascular events in patients with atherosclerotic cardiovascular disease (BNF 2011).
The doses are as follows:
Primary hypercholesterolaemia, combined hyperlipidaemia is 10-20mg daily at night, adjusted at intervals of at least 4 weeks; usual range 10-80mg once daily at night.
Homozygous familial hypercholesterolaemia, 40mg daily at night or 80mg daily in three divided doses (with largest dose at night).
Prevention of cardiovascular events, initially 20-40mg once daily at night, adjusted at intervals of at least 4 weeks; maximum 80mg once daily at night (BNF2011).
Simvastatin 40mg per day is recommended as a first choice lipid lowering drug for primary prevention in adults who have 20% or greater 10 year risk of developing cardiovascular risk (CV). The CV is calculated by a risk calculator or a clinical assessment on the patient's lifestyle, age and ethnic group. (NICE 2008).However, due to limitation in evidence, the authors recommend (Cochrane 2011) a cautious approach when considering whether or not to prescribe statins for primary prevention in people with lower CV risk. The largest single trial of any statin included in a meta-analysis (MA) was done by the Heart Protection Study, and this compared the 40mg dose with a placebo and found a 24% reduction in all major vascular events (Lancet 2002).
A meta-analysis has highlighted the benefits of statins for people with a past history of CV disease (secondary prevention). (Cochrane 2011).The meta-analysis assessed 26 randomised control trials (RCT'S) in patients with or without cardiovascular disease. This study showed that there was a 21% risk reduction in the rate of major vascular events over a year.
The MHRA now recommends that Simvastatin 80mg per day should only be given in patients with severe hypercholesterolaemia at high risk of cardiovascular complications, and patients who have not achieved their target goals at reduced doses of Simvastatin and where the benefits outweigh the risks. (MHRA 2010). The SEARCH STUDY compared 12064 patients over 6.7 years on 80mg/day verses 20mg/day and found the 80mg/day did not show significant benefits over Simvastatin 20mg/day in reducing major cardiovascular events, but patients on the 80mg/day suffered from myopathy (0.9%) and some developed rhabdomylosis (0.2%) compared to none in the 20mg/day (Heart 2007).
The use of statins continues to increase and therefore more and more people suffer from side effects of statins.The two most uncommon but serious side effects are elevation of liver enzymes and various skeletal muscle abnormalities, including mytosis, aching in the shoulder, pain in the jaw, or pain in the muscles of legs. Often pain in the muscle is due to the breakdown of muscle tissue in the body which is eliminated by the body via the kidneys. The waste products then overload the kidneys causing blockage of the kidney, a serious condition called rhabdomyolysis, which can cause death. Patients suffering from rhabdomyolysis have dark red, or cola coloured urine.
Patients suffering from rhabdomyolysis, caution should be exercised as a creatine kinase (CK) level should be measured, before starting treatment in the following situations, elderly(>70 years), patients suffering from renal impairment, uncontrolled hypothyroidism, family history of muscular disorders, any previous history of muscular toxicity with a statin or fibrate or alcohol abuse.
In these situations the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If a patient has previously experienced myopathy on a statin or fibrate, then treatment with a different class of drug should be started with caution on lowest possible doses. If myopathy is suspected and creatine kinase is markedly increased, (five times the upper limit of normal) or muscular symptoms are severe, then treatment should be stopped. In patients with increased creatine levels, who are at increased risk of muscle effects, then statins should not be started. Patients starting statin therapy or whose dose is going to increase should be advised of the risk of myopathy and should report any unexplained muscle pain, tenderness or weakness.
On very rare occasions statins can cause interstitial lung disease and if patients develop dyspnoea, cough, and weight loss, they should seek medical attention. (BNF 2011)
Other side effects include sleep disturbances, headache, dizziness, depression, peripheral neuropathy, amnesia fatigue, sexual dysfunction, thrombocytopenia, visual disturbances, alopecia, and hypersensitivity reactions (including rash, pruritis, urticaria and very rarely lupus erythematosus like reactions) (BNF 2011).
Pharmacodynamics and Pharmacokinetic interactions:
Drug interactions associated with increased risk of myopathy and rhabdomyolysis:
Actions/precautions taken if prescribed:
Potent CYP3A4 inhibitors
Ketoconzole and fluconazol
HIV protease inhibitors (nelfinavir)
Contraindicated with simvastatin
If treatment with statin is unavoidable then statin therapy should be stopped during the course of treatment.
Avoid but if necessary then do not exceed 10mg simvastatin daily
Caution should be used and risk and benefits should be considered, and patients should be monitored.
Simvastatin acid (SVA) increased by 1.9-fold due to the inhibition of the glucuronidation pathway.
Fibrates except for fenofibrate
Dose should not be exceed 10mg of simvastatin daily
Avoid if patient taking high doses of simvastatin, because this can increase in the levels of simvastatin acid (SVA), by the inhibiting action of CYP3A4.
Dose should not exceed 20 mg simvastatin daily
In studies with both Amiodarone and Verapamil there was a 2-3 fold increase in SVA, which can cause myopathy when given with high doses of simvastatin,hence dose should not exceed 20mg.
Patients should be closely monitored and temporary suspension of simvastatin should be considered.
The risk of myopathy may be increased by concomitant administration of Fusidic acid, as isolated cases of rhabdomyolysis have been reported.
Simvastatin dose should not exceed 40mg daily
Patients taking simvastatin 40mg daily reported no increase in myopathy, when taken with Diltiazem but with higher doses there was a 2-7 fold increase in SVA, due to inhibition of CYP3A4, hence dose of simvastatin should not increase 40mg daily.
Avoid grapefruit juice when taking simvastatin
Grapefruit juice inhibits Cytochrome P450 3A4, which increases the SVA by 1.9 folds, hence avoid with simvastatin treatment.
Evidence base to support clinical management plan:
The NICE guidelines suggest that the 40mg per day dose is the most preferred dose in patients who have statin therapy. The largest single trial of any statin was the Heart Protection Study (HPS).This trial compared 40mg/day simvastatin with placebo and found 24% relative reduction in risk of all major vascular events (95% confidence interval (CI)19%-28%, p<0.0001).
The SEARCH study, a double blinded randomised controlled trial (RCT) compared simvastatin 80mg/day to 20mg/day.There were 12064 adults with history of myocardial infraction (MI), for 6.7 years. There was no significant difference in the endpoint of major vascular events and the risk ratio (RR) for 80mg vs. 20mg was 0.94 (95%, CI: 0.88 to 1.01, P=0.10).Unexplained muscle pain, weakness and myopathy was reported in 7% of the people tested in both groups. The effects were more common in the 80mg/day compared to the 20mg/day group. Rhabdomyolysis occurred more often in the 80mg group, but was rare, and 7 cases (0.12%) were reported compared to none for the 20mg group. The endpoint results of the study showed that there was no significant reduction in lowering LDL cholesterol (LDL-C), when simvastatin dose was increased to 80mg/day. (Lancet 2010, 376:1658-69).
A large meta-analysis (MA) assessed 26 RCTs (n=169,138) in patients with or without established cardiovascular (CV) disease. Twenty one RCTs (n=129,526) compared statin therapy with control. Among these, the mean reduction in LDL-C at one year was 1.07mmol/l and the authors calculated that the average relative reduction in rate of major vascular events per 1mmol/l reduction in LDL-C was 21% (95%, CI: 19%-23%, P<0.0001) (LANCET 2010; 376:1670-81). Five trials, including SEARCH compared 80mg/day vs. 20mg/day statin therapy, and the additional mean reduction in LDL-C at one year was 0.51mmol/l (range 0.30-0.65mmol/l) and the RR of major vascular events was reduced by a further 15% overall (95%, CI: 11%-18%, P<0.0001).This study showed that where patients needed a significant reduction in their LDL-C levels, then 80mg/day would be appropriate and beneficial.